Titanium (IV) based anticancer complexes were the first to enter clinical trials following platinum compounds. In particular, budotitane ((bzac)2Ti(OEt)2) and titanocene dichloride (Cp2TiCl2) demonstrated high antitumor activity toward a range of cancer cells; however, these complexes, both containing two labile ligands, were limited by aquatic instability. Therefore, mechanistic aspects remain unresolved, including the nature of the active species and its identification out of the multiple hydrolysis products formed. Vanadium compounds have also been investigated and some derivatives showed high activity. Low stability and rich aqueous chemistry, however, were again limiting factors.
The inventors of the invention have introduced cytotoxic salan Ti (IV) complexes [1-11], which are: (a) substantially more hydrolytically stable than known Ti (IV) complexes; and (b) markedly more active than (bzac)2Ti(OiPr)2, Cp2TiCl2, and cis-platin toward variety of cancer-derived cell lines. Structure activity relationship studies based on both salan and labile ligand variations revealed that reduced steric bulk was favored for cytotoxicity. Additionally, all cytotoxic complexes slowly gave defined oxo-bridged polynuclear hydrolysis products. Direct measurements on the isolated clusters showed no activity.
Additional publications on salan complexes containing labile groups have also been described [12-25].
The inventors have also reported on salan vanadium (V) monoalkoxo compounds, which showed lower stability in water, yet high cytotoxicity [26,32].